Diabetic retinopathy is a common complication of diabetes and a leading cause of blindness in the US and the world. Diabetic macular edema (DME) and retinal neovascularization are the two major pathological alternations leading to the vision loss in diabetic retinopathy. The retinal vascular hyper-permeability or vascular leakage is primarily responsible for DME. Over-expression of vascular endothelial growth factor (VEGF) in the retina plays a crucial role in the BRB breakdown. Currently, there is no effective and noninvasive treatment for DME. A new, non-invasive and cost-effective treatment for DME is needed. It has been found that plasminogen kringle 5 (K5), an 80-amino acid fragment of plasminogen, has the potent anti-angiogenic activity, such as inhibiting the endothelial cell proliferation and migration, which are an important process in angiogenesis. Our previous studies have demonstrated that K5 blocks the VEGF overproduction in the retina and effectively reduces retinal vascular leakage in three independent retinopathy animal models after a single intra-ocular or peri-ocular injection of a low dose. Moreover, the effect of K5 on vascular permeability can be achieved via topical application of K5 eyedrops. These results suggest that administration of this angiogenic inhibitor should have therapeutic effect on DME. We hypothesize that the continuous topical application of K5 eyedrops may become an effective and non-invasive therapy for DME. The objective of this Phase I project is to prove the concept that the K5 eyedrop administration can have long-term therapeutic effect on vascular leakage in the retina of STZ-induced diabetic rats. To obtain the effective concentration of K5 eyedrops for blocking retinal vascular leakage in diabetic rats, we will investigate the pharmacokinetics and distribution of K5 after the administration of K5 eyedrops. Then, we will determine if continuous administration of the K5 eyedrop can result in sustained reduction of retinal vascular leakage in the diabetic rat model. The vascular permeability will be measured by the Evans blue-albumin and fluorescein-albumin leakage methods. The Phase I project will not only address the feasibility to use K5 eyedrops for the treatment of DME, but also generate essential data and lay a solid ground for the development of a marketable product in the Phase II studies. Our long-term goal is to develop a novel, noninvasive, effective therapy for DME.